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Glycine to alanine mutations affect the structure and dynamics of micelle bound alpha-synuclein

GLYCINE TO ALANINE MUTATIONS AFFECT THE STRUCTURE
AND DYNAMICS OF MICELLE BOUND α-SYNUCLEIN
by
Adithya Balasubramanian
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2008
Copyright 2008 Adithya Balasubramanian

Parkinson's disease has been associated with misfolding of the protein alpha-synuclein (aS). Previous studies of micelle bound alpha-synucleins have shown that it forms two anti-parallel helices on the micelle surface with elevated dynamics in the glycine residues of the III, V, and VI repeat of its amino acid sequence. Thus by mutating these residues to alanine a significant change in the dynamics and structure has been observed. A better micelle system has been established using sodium lauroyl sarcosine (SLS) which has more aggregation number than SDS and decreases the negative restraint on the C-alpha chemical shifts. Two aS variants, aSG(III) with mutated Gly residues at 31, 36 and 41 mutated to Ala and aSG(II) with mutated Gly residues at 67 and 68 to Ala are studied. Backbone and dynamic parameters of the variants show that there is an increase in chemical shift causing an increment in helical character in the regions of mutation. But this is been compensated at other distant residues where the same character is significantly reduced. Similar pattern is observed in the dynamic parameters which show an increase in rigidity of the helix in the mutated regions. These strong increase in chemical shift and decrease in dynamics suggest that the glycine residues in these positions play a significant role in the interaction of the protein alpha-synuclein with the lipid surfaces.

GLYCINE TO ALANINE MUTATIONS AFFECT THE STRUCTURE
AND DYNAMICS OF MICELLE BOUND α-SYNUCLEIN
by
Adithya Balasubramanian
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2008
Copyright 2008 Adithya Balasubramanian